This proposal brings together investigators with great expertise in tobacco carcinogenesis and genome wide association studies to investigate ethnic/ racial differences in lung cancer due to cigarette smoking. Among cigarette smokers, African Americans and Native Hawaiians have a higher risk, while Japanese Americans and Latinos have a lower risk for lung cancer than European Americans. We hypothesize that these differences in lung cancer susceptibility are due to ethnic and racial variations in exposure and response to cigarette smoke carcinogens. This hypothesis will be tested through a unique combination of genetic, biomarker, and mechanistic studies using innovative techniques and relying on superb internationally recognized expertise. If this hypothesis is supported, our mechanistic understanding of tobacco-induced lung cancer will increase immensely, thus providing important new insights for lung cancer prevention. Project 1, Multiethnic Genome Scan of Metabolic Phenotypes will examine the association of common genetic variants with phenotypic biomarkers of tobacco smoke constituent uptake and metabolic activation in different ethnic/racial groups. A genome wide association study of five ethnic/racial groups (450 subjects per group) will be carried out and the results integrated with those of tobacco smoke constituent biomarkers for nicotine and carcinogens. The highly integrated Projects 2-5 will collaborate with Project 1 and use the superb expertise of the project leaders to study the relevant mechanisms. Project 2, Nicotine and NNK Glucuronidation Pathways in Smokers, will investigate ethnic differences in the metabolism of nicotine and the tobacco-specific lung carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), focusing on the crucial glucuronidation detoxification pathway. Project 3, Ethnic/Racial Differences in 1,3-Butadiene Metabolism and DNA Adduct Formation, will focus on ethnic and racial differences in the metabolism of 1,3- butadiene. Project 4, Ethnic/Racial Differences in DNA Repair, will investigate the critical role of DNA repair in protecting against mutagenicity and carcinogenicity of cigarette smoke carcinogens. Project 5, Metabolism of NNK among African Americans, will directly test the hypothesis that there are ethnic and racial differences in the metabolism of the tobacco-specific lung carcinogen NNK. The projects will be supported by three Cores: A, Administrative; B, Tobacco Smoke Constituent Biomarker; and C, Biostatistics. The unique combination of expertise in this program project forms a powerful team arguably unmatched in its ability to address mechanisms of lung cancer development in smokers from different ethnic/racial groups.